West Nile virus (WNV) is a mosquito-transmitted flavivirus that causes severe neurological disease is humans and other animals. WNV recently emerged in the USA and continues its spread in the Americas, thus placing millions of people at risk of infection, development of neurologic disease, and death. The host immune processes that control WNV infection are not fully understood. The innate immune response against WNV is critical for controlling infection, and has been modeled in traditional inbred mouse lines but these inbred models lack the genetic diversity present in human populations and thus are limited in their ability to evaluate the full range of WNV disease and immune outcomes. We have therefore evaluated WNV disease susceptibility and host innate immune responses to WNV infection in the Collaborative Cross (CC) model. Our studies show that unlike inbred mouse populations, the CC captures the full range of WNV pathogenesis and outcomes observed in humans. Our preliminary studies have now identified unique quantitative trait loci (QTL) encoding host genes that are linked to immune-regulatory phenotypes of WNV control. Thus, we will conduct the following Aims to: 1) Apply the CC to identify gene(s) regulating peripheral viral control in the spleen, and 2) define novel virus stimulated genes (VSG) in the CC that control neuroinvasion and neuropathogenesis of WNV infection.